Behavioral and physiologic studies suggest that the prefrontal cortex selects relevant signals and suppresses noise, which is essential for focusing on the task at hand and ignoring distracters. The goal of the proposed studies is to investigate the largely unexplored synaptic circuits that underlie these processes, using as a model system the robustly interconnected anterior cingulate cortex (ACC), the dorsolateral prefrontal cortices (DLPFC) and the auditory association cortices, which have a demonstrated role in excitatory and inhibitory control. The working hypothesis is that pathways that interlink these areas interact differentially with excitatory neurons and distinct classes of inhibitory neurons, in circuits that allow functional diversity for flexible behavior. This hypothesis is based on a conceptual model of cortical connections and their relationship to distinct neurochemical and functional classes of inhibitory neurons summarized by two principles: (1) Corticocortical connections have characteristic laminar origins and terminations that can be predicted by the structural architecture of the linked areas. (2) Connections originate and terminate in laminar microenvironments that vary significantly in the density of neurochemical and functional classes of inhibitory neurons. Experiments are designed within this conceptual framework to investigate: the synaptic specificity of pathways that link auditory association cortices with the functionally distinct ACC and DLPFC; the synaptic circuits that link the functionally distinct ACC and DLPFC with each other, as well as with their respective neighboring and functionally related areas; the projections of both ACC and DLPFC to the premotor cortex, in pathways that may underlie decision for action. Prefrontal pathways will be labeled with neural tracers, combined with double- or triple labeling for distinct neurochemical classes of inhibitory neurons, molecular markers or receptors. Brain tissue will be processed for correlated light and electron microscopic analysis, synaptic reconstruction and quantitative analyses. Information from this study will provide a foundation to understand the role of the prefrontal cortex in central executive functions, and the resulting imbalance in excitatory and inhibitory control in neurologic and psychiatric diseases affecting prefrontal-temporal pathways, including schizophrenia and autism. PUBLIC HEALTH RELEVANCE: Disruption in the balance of excitation and inhibition underlies the deficits in several neurologic and psychiatric diseases. Damage to the prefrontal cortex results in loss of the ability to filter out noise in auditory processing in humans. The dorsolateral prefrontal cortex, anterior cingulate and temporal auditory cortices are affected in schizophrenia, consistent with the auditory nature of hallucinations, distractibility and debilitating deficits in cognition. In autism, prefrontal and cingulate circuits involved in response inhibition are underactive and poorly synchronized. Investigation of the excitatory and inhibitory synaptic interactions within this integrated cortical circuit will have important implications for the development of therapeutic interventions for neurologic diseases, schizophrenia and autism.